Accumulation of neurofilaments in neuronal cell bodies is a pathologic hallmark of several neurodegenerative diseases associated with aging, including Pick's disease, corticobasal degeneration, and ALS. This abnormal accumulation may be due to defects in neurofilament slow axonal transport, the process by which cytoskeletal proteins are transported down the axon. Slow axonal transport of cytoskeletal proteins is necessary for the maintenance of the integrity and morphology of neuronal processes during adulthood. The molecular mechanisms for slow axonal transport are not yet understood. New data described in the preliminary data section of this grant show that neurofilaments are associated with microtubule motors and that neurofilaments can translocate bidirectionally along microtubules in vitro. At least part of this motility is due to the activity of cytoplasmic dynein, which has been found associated with slow axonal transport components in axons. The goal of this project is to use cell biological studies to assess whether the observed in vitro motility of neurofilaments along microtubules is related to the in vivo transport of neurofilaments down axons. The focus of these studies fits topic area 12 in the program announcement: Extracellular matrix and cytoskeleton. In particular, this proposal is relevant to age-related changes in intracellular transport mechanisms that may relate to abnormal accumulation of cytoskeletal proteins in neuronal cell bodies in neurodegenerative diseases.